LAUSR

The Histone Deacetylase 6 (HDAC6) enzyme has two deacetylase domains and is found almost exclusively in the cytoplasm. It deacetylates targets such as tubulin, cortactin, HSP90, KU70 and potentially the Treg-specific transcription factor FOXP3 but not histones under physiological conditions. COPD frequent exacerbators (COPD-FE) data suggest increased activity of HDAC6 and preclinical literature suggests HDAC6 inhibition/depletion rescues cilia shortening, mucociliary clearance defects and pulmonary barrier integrity, thus reducing susceptibility to acute lung injury. Additional literature describes functions in PAH, CF and IPF as well as non-pulmonary indications, with protection from various inflammatory diseases. Here we present the characterization of HDAC6 inhibitors in primary human bronchial epithelial cells grown at the air-liquid interface and Hdac6 KO mice in two preclinical models of COPD (elastase/LPS and cigarette smoke). HDAC6 inhibition and deficiency reduce mucus production and persistence of inflammation both in mice and in 3D human respiratory epithelia, with strong evidence for reducing MUC5AC positive cells as well as Mmp9 expression and neutrophilic inflammation. Thus, HDAC6 represents a solid pharmacological target with the potential to benefit COPD-FE patients, especially if suffering from chronic mucus hypersecretion. Method: H. Meier, F. Kolling, J. Auburger, L. Schneider, C. Noack, L. Dietz, D. Urrego, S. Schroder, I. Hagelschuer, T. Kramer